ETOP 7-14 NICHE Appendix 1: Patient Information (English) page 1 of 9V1.0 01 Dec 2014 <insert center name>

ETOP 7-14 NICHE

Afatinib in pretreated patients with advanced NSCLC harbouringHER2 exon 20 mutations

1) This template Patient Information Sheet and Informed Consent has been written accordingto ICH guidelines which state the Informed Consent should adhere to GCP and to the ethicalprinciples that have origin in the Declaration of Helsinki.

2) This template can be edited to incorporate information specific to your institution. Pleaseforward the edited version to the ETOP Coordinating Office for approval. Submit to the EthicsCommittee/IRB only after approval by the ETOP Coordinating Office. The final version musthave received the IRB/Local Ethics Committee approval in advance of use.

3) Following the ICH-GCP guidelines, the Informed Consent should contain informationabout the following items:

a) The trial involves research

b) Purpose of the trial

c) Trial treatment(s) and the probability of random assignment

d) The subject’s responsibilities

e) The aspects of the trial that are experimental

f) Risks

g) Benefits

h) Alternative treatments available

i) Compensation/expenses

j) Subject’s participation is voluntary/right to withdraw

k) Confidentiality

l) Information about course of the trial

m) Circumstance under which trial may be terminated

n) Contact persons for further information or in case of injury

o) The approximate number of subjects involved in the trial

p) Duration of subject’s participation in the trial

q) Version number and date

4) This template has been designed to cover the above items. If the IRB/Local EthicsCommittee requires modifications, none of the above items should be completely excluded,nor should the meaning of the highlighted areas be modified. Such modifications must besubmitted to ETOP for approval.

5) In order to assist in the preparation of your customized version, an electronic file in MSWord will be distributed via e-mail to all Principal Investigators or ETOP members maydownload it from the ETOP web site (www.etop-eu.org).

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PATIENT INFORMATION SHEET AND INFORMED CONSENT APPENDIX 1

ETOP PATIENT INFORMATION SHEET FOR CLINICAL RESEARCH

Dear patient,

You are being asked to participate in a clinical research study. The doctors atdifferent centers of the European Thoracic Oncology Platform (ETOP) and in othercooperative groups or centers throughout the world study the nature of lung cancerand attempt to develop improved methods of diagnosis and treatment. This is calledclinical research. In order to decide whether or not you should agree to be part of thisresearch study you should understand enough about its risks and benefits to makean informed judgment. Your participation in this research study is entirely voluntaryand you will be given sufficient time to decide whether you wish to participate. Thisprocess is known as Informed Consent.

This Patient Information Sheet gives detailed information about the research study,which your doctor will discuss with you. Once you understand the study, if you wishto participate, you will be asked to sign the Patient Informed Consent. You will have acopy of this document and of the Patient Informed Consent to keep as a record.

The clinical research study being proposed to you is:

ETOP 7-14 NICHE

Afatinib in pretreated patients with advanced NSCLC harbouringHER2 exon 20 mutations

PURPOSE OF THE RESEARCH STUDYYou have been diagnosed with a type of lung cancer that is called “non small celllung cancer (NSCLC)”. Your lung cancer has recently relapsed despite previoustreatment with chemotherapy. Relapsed means that, despite treatment, the cancer isgrowing. Your doctor has decided that further treatment of your cancer is necessary.Previous clinical studies of NSCLC have shown that patients with tumors harboringspecific gene mutations (changes) in the epithelial growth factor receptor (EGFR) oranaplastic lymphoma kinase (ALK) showed better results after treatment withtyrosine kinase inhibitors (TKI), like afatinib (tradename Giotrif®) , compared withclassical treatment with chemotherapy. The treatment with TKI has become a newstandard-of-care for patient with advanced lung cancer and EGFR or ALK changes.Several novel mutations, which are candidates as targets for specific medicationhave been discovered. Human epidermal growth factor 2 (HER2, erbB-2/neu) is aprotein of the so called ErbB family (including HER2 [ErbB2], ErbB3 and ErbB4).These proteins are involved in the growth and spread of cancer cells. Mutations inHER2 are found in about 2% of the NSCLC.

Afatinib works by blocking the activity of the ErbB family proteins and can inhibitgrowth and spread of cancer cells.

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The aim of the current study is to investigate the control of disease in pretreatedpatients with advanced NSCLC harbouring HER2 exon 20 mutations as well as thesafety and tolerability (how severe the side effects are) of the treatment with afatinib.

Afatinib is approved by the European and the Swiss Medicines Agencies for thetreatment of adult patients with a specific type of cancer of the lung (non-small celllung cancer) that is identified by a change (mutation) in the gene for EGFR as firsttreatment or if prior chemotherapy treatment has been insufficient.

A total of 22 patients from centers around Europe are expected to be enrolled in thisstudy over a period of 24 months. In country it is planned that xx patients will takepart. All patients will be treated in the same way. The study will take approximately 40months to be completed.

This clinical trial is conducted according to the applicable national laws andinternational guidelines. The trial has been approved by the independent EthicsCommittee concerned insert name of the Ethics Committee.

DESCRIPTION OF THE CLINICAL RESEARCH STUDY

If you decide to participate in the study and meet the criteria to take part in the study,you will receive the following treatment:

Afatinib 40 mg orally, daily. You will take afatinib tablets every day. Tablets should betaken at a fixed time each day and at least 1 hour before or 3 hours after theingestion of food.

Inpatient admission into a hospital is not envisaged, but can potentially becomenecessary.

In order to determine if you can participate in this trial a piece of your tumor, that hasbeen removed at the time of diagnosis, must be available for later central review ofHER2 mutation

You will have a full medical history taken, physical examination, radiological and labworkout performed at the time you enter the study. If you are a female of child-bearing potential, a pregnancy test will be done.

During the study treatment, you must visit your treating physician every 3 weeks forthe first 12 weeks, then every 4 weeks for a physical examination. Please take withyou all empty, full and partly used boxes of afatinib tablets. Routine blood and urineanalyses including liver and kidney function will be carried out every 3 or 4 weeksrespectively, as part of standard medical routine. If you develop side effects, morefrequent examinations may be necessary.

Your physician will document your general condition and all hospital stays during theclinical trial. He/she will similarly ask you about all side effects, which youexperienced and about all medications or treatments, which you received since yourlast visit.

To determine the status of your lung cancer and effects from the treatment,radiological examinations (computer tomography (CT) of the chest) will be conductedevery 6 weeks (week 6 and 12) and later every 8 weeks until your tumour grows

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again. These examinations are carried out as part of medical routine and can beperformed more frequently, if your treating physician considers this appropriate.

Your doctor may suggest other tests, such as CT of the brain. The regular doctor’svisits are part of your standard medical care and are handled the same way as if youdid not take part in the study.

If you participate in the study, you should follow the instructions of your treatingphysician, follow the schedule of treatment visits, record on the patient diary theafatinib tablets taken, inform your physician of any new signs and symptoms, and anynon-study medication you take.

VOLUNTARY PARTICIPATION/RIGHT TO REFUSE OR WITHDRAW

Your participation in this research study is entirely voluntary. If you decide not toparticipate in the study, this will not affect your medical care in any way. If you beginthe study, you will have the right to withdraw at any time without giving any reason.This will not affect your future medical assistance. You will be asked to have a finalexamination before you withdraw and you will be advised for other available carewhich suits your needs and medical condition. If you should withdraw, data alreadycollected until then will be used for analysis.

RISKS AND DISCOMFORTSWhile you receive protocol treatment, you are at risk of side effects. Your physicianwill be checking you closely to see if any of the side effects are occurring. You shouldreport any side effect or symptom that you experience to your physician. Other drugsmay be given to make some of these side effects less serious and uncomfortable.

Afatinib side effects:

Very common (≥ 10%):• Diarrhoea• Skin rash• Mouth sores and inflammation• Nail infection• Decreased appetite• Bleeding from the nose

Common (1 – 10%):• Pain, redness, swelling or peeling of the skin of your hands and feet• Increased levels of the liver enzymes in blood tests.• Inflammation of the lining of the bladder• Abnormal taste sensations (dysgeusia)• Stomach pain, indigestion, heartburn• Lip inflammation• Decreased weight• Runny nose• Muscle spasms• Fever

Rare (< 1%)• Inflammation of the lungs called “interstitial lung disease”• Eye irritation or inflammation

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Your physician will be checking you closely to see if any of these side effects areoccurring. Your doctor may prescribe medication to keep these side effects undercontrol.

You should tell your doctor: If you have diarrhoea lasting more than 2 days. Diarrhoea may lead to fluid

loss (common, may affect up to 1 in 10 people), low blood potassium(common) and worsening kidney function (common). Diarrhoea can betreated. At the first signs of diarrhoea drink plenty of fluids. You should haveantidiarrhoeal medicine available prior to taking afatinib.

If a rash starts. If treatment for rash is not working and the rash is getting moresevere (for example, you have peeling or blistering of the skin) you shouldnotify your doctor immediately, since your doctor may decide to stop yourtreatment with afatinib. Rash may occur or worsen in areas exposed to sun.Sun protection with protective clothing and sunscreen is recommended.

If you develop new or sudden worsening of shortness of breath, possibly witha cough or fever.

If you have sudden onset or worsening of eye symptoms such as pain orredness or dry eye.

Pregnancy/Birth Control:

All women who participate in the trial and are able to become pregnant must useeffective contraception while they receive study medication.

You will not be allowed to enter this study if you are pregnant, plan to becomepregnant, or if you are breastfeeding. This is because the effects of the study drug onan unborn baby or nursing infant are uncertain. While you are taking afatinib tabletsand for at least 28 days after the last dose you will also be asked to use one of therequired contraceptive methods (a way to prevent you from becoming pregnant).Your doctor will discuss with you which methods constitute effective contraception.

If you become pregnant, you must tell your study doctor immediately so that he/shemay discuss with you the possibility of stopping study treatment. Your doctor willneed to report this information and the outcome of your pregnancy to the ETOPsafety office.

If you are a man whose partner can get pregnant, you and your partner will need touse birth control during afatinib treatment and for at least 1 month after the last dose.If your partner becomes pregnant while you are receiving study medication, tell yourstudy doctor immediately as they will need to report the outcome of the pregnancy tothe ETOP safety office.

BENEFITS

The ultimate goal of conducting clinical research studies in lung cancer patients is tobetter understand the behaviour of cancer and to find better ways of treatment. Wehope that the treatment under this clinical research study will be of benefit to youand/or that it will help others, although we cannot guarantee this.

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ALTERNATIVE TREATMENTS

Instead of being in this study, your doctor may recommend that you receive otherform of treatment or chemotherapy not given as part of this study.

EXPENSES / REMUNERATION

Afatinib will be provided free of charge by Boehringer Ingelheim

All other expenses, for example, routine standard examinations, will be handled as ifyou were receiving standard treatment and not participating in the clinical study.

You will receive no payment for taking part in this study.

INSURANCE

ETOP has concluded the appropriate liability insurance for this study (insert policynumber if required according to local guidelines). Patients, who may suffer injuriesdue to the study, should report it immediately to their doctor, who will take thenecessary steps.

CONFIDENTIALITY

The researchers will need to collect personal information from you such as your age,gender and relevant health information. All information collected is coded in a waythat without a key it will not be possible to link the information to your person.

Any personal or health information that is collected will be kept private andconfidential. It will be stored securely. Only authorised persons, who understand thatit must be kept confidential, will be able to get access to it. In any report of theresearch made available to the public you will not be referred to by name.

Representatives of the project sponsor, ethics committees or drug regulatoryagencies may require access to personal or health information contained in yourmedical records to verify clinical trial procedures and/or data. Your personal data willbe stored in a database and evaluated at ETOP Coordinating Office. ETOPguarantees that the national and international data protection guidelines arerespected.

COLLECTION OF BIOLOGICAL MATERIALAbout Using Tissue for Research

In order for you to participate in this study, we need to be sure of the type of lungcancer that you have. Your doctor will be required to send a sample of tumour thatwas collected either when you were first diagnosed or when you had the relapse to acentral laboratory at the Medical University of Gdansk, Poland. The central laboratoryperforms a pathology review and tests the sample of your tumour for the HER2mutation.

In addition, we would like to keep this tissue for future research. If you allow the useof this tissue, it will be kept at the central laboratory at the Medical University of

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Gdansk, Poland and used under the responsibility of the Foundation Council of theETOP.

Your tissue will be very helpful for future research. The research that may be donewith your tissue is not designed specifically to benefit you. It may have an impact onthe choice of a specific treatment for this type of lung cancer for others. Bybroadening the knowledge about lung cancer, it might help other patients.

The research will not have an effect on your medical care. We will not examine ifcancer is hereditary in your family. In the unlikely case that information relevant toyou comes up in the future, we will contact your doctor.

The choice to let us keep the left over tissue for future research is up to you. Nomatter what you decide to do, your choice will in no way affect the quality ofyour care.

If you decide now to allow ETOP to use your tissue for research, you can changeyour mind at any time. Just contact your doctor and let him/her know that you do notwant ETOP to use your tissue any longer. Then, any tissue that remains will be sentback to the pathologist at your hospital.

The ultimate goals of research using tissue include learning more about what causeslung cancer or other diseases, how to prevent it, and how to treat it.

There are no risks related to research with your tissue. We will make sure that yourpersonal information will be kept private.

TERMINATION OF THE STUDY

You might stop receiving study treatment without your consent for the followingreasons:

a) If your lung cancer worsens or a new tumour develops.

b) If the doctors treating you detect side effects that they consider dangerous.

c) If you refuse to have the treatments or follow-up examinations and testsneeded to determine whether the treatment is safe and effective.

d) If the early analyses of study data show insufficient benefit or a significantpotential harm of the treatment.

e) If the sponsor ETOP decided to stop the study.

NEW INFORMATION ARISING FROM THIS AND OTHER STUDIES

You have the right to be informed of the progress of the research study and of its finalresults. You have also the right to be informed of all additional results of otherstudies, which might be important for your treatment or might affect your willingnessto continue.

CONTACT PERSONS

The physician in charge of this study is (give name, telephone number of PI). If you needmore information about this study before you decide to join, or at any other time, youmay wish to contact him/her. In the event that you do decide to participate, he/sheshould also be called if there are severe side effects from the treatment.

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PATIENT INFORMED CONSENT FOR CLINICAL RESEARCH

TITLE: ETOP 7-14 NICHE

Afatinib in pretreated patients with advanced NSCLC harbouring HER2 exon 20mutations

STATEMENT OF PHYSICIAN OBTAINING INFORMED CONSENT

I have fully explained this clinical research study to the patient____________________.

In my judgment, and that of the patient, there was sufficient access to information,including risks and benefits, to make an informed decision.

DATE: _____________________

PHYSICIAN’S SIGNATURE:

______________________________________________

PHYSICIAN’S NAME:

____________________________________________________

PATIENT’S STATEMENT

I confirm that I have read and understood this Patient Information Sheet dated dd-mmm-yyyy for the ETOP 7-14 NICHE study. I had the opportunity to discuss theclinical study with the undersigning physician, ask questions and I am satisfied withthe answers that I have received.

I understand the purposes, procedures and risks of this research project as describedin the Information Sheet.

I was informed about alternative treatment options.

I had sufficient time to take the decision.

I take note that a sample of my tumour tissue will be collected, sent to the centrallaboratory at the Medical University of Gdansk, Poland, and used for the purpose ofquality assurance (central pathology review) and review of HER2 mutation status.

I take note that future cancer research with my biological material will only be doneafter approval by the relevant ethics committee.

Please choose one:

□ I allow the use of my tissue sample for future cancer research.

□ I do not allow the use of my tissue sample for future cancer research.

I take note that any research will be such that my privacy will be fully protected

I am informed that an injury as a result of participating in this research project iscovered by an insurance.

I agree that my General Practitioner will be informed of my participation in this study

I freely agree to participate in this project according to the conditions in the PatientInformation Sheet. I understand that I withdraw my consent any time without givingany reasons and that this will not affect my future medical care.

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I understand that my personal data leaves the hospital only in anonymised form andthat the researchers will not reveal my identity and personal details if informationabout clinical study is published. For quality control and inspections I give permissionto individuals from ETOP, to staff from the health authorities and ethics committeesfor to have access to my medical records. In such cases personal information willalways remain confidential.

I am aware that the procedures and restrictions described in the Patient InformationSheet have to be followed.

In the interest of my personal health the researcher can take me off the study.

I have received a copy of the Patient Information Sheet and Consent.

DATE: ______________________ [Date must be written by the patient]

PATIENT’S SIGNATURE:_______________________________________________

PATIENT’S NAME: ____________________________________________________

PATIENT’S DATE OF BIRTH:____________________________________________

Patient ID number assigned at randomization:_______________________________

PLEASE KEEP A COPY OF THE SIGNED INFORMED CONSENT. DO NOT SENDTHE SIGNED INFORMED CONSENT FORM TO ETOP.